IT202300006819A1 - PROCESS FOR PREPARING PRALSETINIB IN AMORPHOUS FORM, AND RELATED INTERMEDIATES IN CRYSTALLINE FORM. - Google Patents

Description

PROCESS FOR PREPARING PRALSETINIB IN AMORPHOUS FORM, AND RELATED INTERMEDIATES IN CRYSTALLINE FORM

Field of invention

The present invention relates to a process for preparing pralsetinib in amorphous form. The present invention also relates to related intermediates in crystalline form.

Prior art of the invention

The Food and Drug Administration (FDA) granted accelerated approval for pralsetinib on September 4, 2020 for non-small cell lung cancer (NSCLC) and on December 1, 2020 for thyroid cancer, for: (i) adult patients with metastatic RET fusion-positive NSCLC, (ii) adult and pediatric patients aged 12 years and older with metastatic or advanced RET-mutant medullary thyroid cancer requiring systemic therapy, and (iii) adult and pediatric patients aged 12 years and older with metastatic or advanced RET fusion-positive thyroid cancer requiring systemic therapy and who are refractory to radioiodine (if radioiodine is appropriate).

The synthesis of pralsetinib and its intermediates is described in WO 2017/079140 A1 and WO 2022/120136 A1 by

Additionally, polymorphs and salts of pralsetinib were studied. For example, WO 2021/243192 A1 describes crystalline forms A, B, C, F, G, J, K, L, M, N, P, 5-A, 5-B and 5-C of pralsetinib.

WO 2022/086899 A1 describes the crystalline forms of pralsetinib I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII. Forms CM-I, CM-II, CM-III, CM-IV, CM-V, CM-VI, CM-VII and CM-VIII are described in CN111777595A. In WO 2022/117448 A1 the crystalline forms II and HyB of pralsetinib are mentioned.

WO 2021/243192 A1 further describes several salts of pralsetinib with other acids, such as benzene sulfonic acid, methane sulfonic acid, hydrochloric acid, hydrobromic acid, nitric acid, pyruvic acid, citric acid, fumaric acid, maleic acid, salicylic acid, glutaric acid, sulfuric acid, tartaric acid, phosphoric acid and succinic acid.

Furthermore, cocrystals of pralsetinib are described in WO 2021/243192 A1. In particular, cocrystals with 4-aminobenzoic acid, 4-hydroxybenzoic acid, benzoic acid, vanillic acid, quercetin dihydrate, gentisic acid, saccharin and urea are reported.

Finally, solvates of pralsetinib are known. For example, solvates with tetrahydrofuran (THF), chloroform, cyclohexane, methanol are described in WO 2021/243192 A1 and a solvate with dimethyl sulfoxide (DMSO) is described in WO2022117448A1.

However, the processes for the preparation of pralsetinib salts as described in the prior art have several disadvantages, for example: large volumes of solvents are used and the reactions are carried out at high temperatures. The yield and quality of the salts, which generally require a long time to form, are not clearly described in the prior art. For these reasons, the process and the salts described in the prior art are not feasible at an industrial level.

For the amorphous form of pralsetinib, the corresponding preparation process by distillation with chloroform is described in WO 2021/243192 A1. This process leads to the formation of the amorphous forms of pralsetinib, however a substantial amount of chloroform remains trapped. For this reason, the control of residual chloroform within 60 ppm as per the ICH limit could be challenging. Furthermore, the process according to WO 2021/243192 A1 is not an industrially feasible process.

For all the above reasons, there is a strong need to develop an industrially feasible and simpler process to produce pralsetinib in amorphous form, requiring reduced solvent volumes and low processing temperatures and allowing to obtain very high purity and yields.

Summary of the invention

The present invention relates to a process for preparing pralsetinib in amorphous form, which involves the use of pralsetinib salts or co-crystals as crystalline intermediates.

According to a first aspect, the present invention relates to a process for the preparation of pralsetinib of Formula I:

in amorphous form, as defined in claim 1.

According to a further aspect, the present invention relates to crystalline compounds containing pralsetinib with an acid selected from: (1S)-(+)-10-camphorsulfonic acid (CSA), trifluoroacetic acid (TFA) and pyroglutamic acid (PGA), as defined in the appended claims.

Advantageously, the Applicant has found that the reaction to obtain the crystalline compounds containing pralsetinib with the above acids is faster than the reaction to obtain other salts and requires low temperatures, thus leading to very good yields and quality of the crystalline intermediates obtained. Furthermore, these crystalline compounds containing pralsetinib are isolated as solids and for this reason it is easier to handle them on a large scale. The use of these intermediates allows to obtain pralsetinib as an active pharmaceutical ingredient (API) in an amorphous form of very high quality.

The process according to the present invention, when compared to the processes for obtaining pralsetinib in amorphous form known in the art, is advantageous with respect to several aspects.

In particular, the process of the invention allows to obtain a solvent-free product, therefore it will be easy to satisfy the requirements set by the ICH regulation.

Furthermore, the process of the present invention can be readily carried out on an industrial scale.

Brief description of the drawings

Figure 1: XPRD pattern of the crystalline salt form of pralsetinib with CSA of Formula V.

Figure 2: TGA of the crystalline salt form of pralsetinib with CSA from Formula V.

Figure 3: XPRD pattern of the crystalline form of pralsetinib salt with TFA of Formula VI.

Figure 4: TGA of the crystalline salt form of pralsetinib with TFA of Formula VI.

Figure 5: XRPD pattern of the crystalline form of pralsetinib cocrystal with PGA of Formula VII.

Figure 6: TGA of the crystalline form of pralsetinib cocrystal with PGA of Formula VII.

Figure 7: XRPD pattern of pralsetinib Formula I in amorphous form.

Detailed description of the invention

In the description and claims that follow, the definitions of numerical ranges include the individual values within the range itself and the corresponding extremes, unless otherwise specified.

In the description and claims that follow, the term “comprise” also includes the terms “consisting of” or “consisting essentially of”.

The present invention relates to a process for preparing pralsetinib of Formula I,

Formula I

in amorphous form, said process comprising:

a) react a compound of Formula II

Formula II

with a base in a solvent to obtain a compound of Formula III

Formula III,

where the solvent is chosen from an organic solvent, water or a combination thereof;

b) isolate the compound of Formula III at a pH ranging from 2 to 9;

c) react the isolated compound of Formula III with a compound of Formula IV

Formula IV

in the presence of a coupling agent, a base and a polar aprotic solvent to obtain pralsetinib in solution form;

d) isolate a crystalline compound containing pralsetinib by reacting pralsetinib in the form of a solution obtained in step c) with an acid selected from: (1S)-(+)-10-camphorsulfonic acid (CSA), trifluoroacetic acid (TFA) and pyroglutamic acid (PGA); e) suspend the isolated crystalline compound containing pralsetinib obtained in step d) in a solvent selected from alcohols, esters, aromatic hydrocarbons, chlorinated solvents or mixtures thereof, and add to the suspension thus obtained a basic solution to obtain a solution of pralsetinib as the free base;

f) isolate pralsetinib in amorphous form from the pralsetinib free base solution obtained in step e).

With reference to step a), the base is preferably selected from: sodium hydroxide (NaOH), lithium hydroxide (LiOH) and potassium hydroxide (KOH). The organic solvent used in step a) is preferably selected from: alcohols, ethers. Preferably, when the solvent is an alcohol, it is selected from methyl alcohol (MeOH), ethyl alcohol (EtOH). Preferably, when the solvent is an ether, it is tetrahydrofuran (THF). Solvent mixtures are preferably selected from: THF/water, THF/EtOH/water, EtOH/water and MeOH/water. Preferably, the solvent mixture is THF/EtOH/water. According to a preferred aspect, in step a) the solvent is selected from: alcohols, preferably methyl alcohol (MeOH) or ethyl alcohol (EtOH); ethers, preferably tetrahydrofuran (THF); and water, or mixtures thereof.

According to a preferred embodiment, the compound of Formula II is reacted in step a) with a base at a temperature of 25°C to 70°C, preferably 50°C to 60°C.

With reference to step b), the pH is preferably from 2 to 5. As known to those skilled in the art, the pH value can be obtained by adding an acid, preferably hydrochloric acid (HCl).

As regards step b), the isolation of the compound of Formula III is preferably carried out by crystallization or precipitation. For this purpose, a solvent is added, which is preferably selected from alcohols and ketones. Preferably, when the solvent is an alcohol, it is selected from MeOH, EtOH or isopropyl alcohol (IPA), when the solvent is a ketone, it is preferably acetone. Preferably, the solvent is MeOH. According to a preferred aspect, wherein in step b) the isolation occurs by crystallization or precipitation, adding a solvent selected from: alcohols, preferably MeOH, EtOH or isopropyl alcohol (IPA); and ketones, preferably acetone; or mixtures thereof.

With reference to step c), the coupling agent is preferably selected from benzotriazole-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBOP), N,N,N?,N?-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate (TBTU), N-ethyl-N?-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU). Preferably, the coupling agent is PyBOP.

With reference to the base in step c), it is preferably chosen between N,N-diisopropylethylamine (DIPEA) or triethylamine (TEA). Preferably, the base is DIPEA.

With reference to the polar aprotic solvent of step c), it is preferably chosen from: N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF) or mixtures thereof. Preferably, the polar aprotic solvent is DMAc.

Most preferably, the compound of Formula III is reacted with the compound of Formula IV in step c) using PyBOP as the coupling agent, DMAc as the polar aprotic solvent, and DIPEA as the base.

The crystalline compound containing pralsetinib from step d), which can be used as an intermediate in the above process, can be represented by one of the following formulas:

Formula V

Formula VI

Formula VII

in which the Formula V intermediate is pralsetinib/CSA salt, the Formula VI intermediate? pralsetinib/TFA salt and the intermediate of Formula VII ? pralsetinib/PGA cocrystal.

With reference to step d), the acid is preferably trifluoroacetic acid (TFA) to obtain the crystalline compound containing pralsetinib of Formula VI.

For step d), when the crystalline compound containing pralsetinib is of Formula V, the isolation is obtained by adding a solvent selected from alcohols, esters, nitriles and water, or mixtures thereof. When the solvent is an alcohol, it is preferably selected from MeOH and EtOH, more preferably MeOH. When the solvent is a nitrile, it is preferably acetonitrile (ACN). When the solvent is an ester, it is preferably ethyl acetate (EtOAc). Preferably, the solvent mixture is selected from MeOH/water and ACN/water.

When the crystalline compound containing pralsetinib is of Formula VI, the isolation according to step d) is obtained by adding a solvent selected from: esters, nitriles, ethers, chlorinated solvents, and water, or mixtures thereof. When the solvent is an ester, it is preferably ethyl acetate (EtOAc). When the solvent is a nitrile, it is preferably ACN.

When the solvent is a chlorinated solvent, it is preferably dichloromethane (DCM). When the solvent is an ether, it is preferably tert-butyl methyl ether (MTBE). Preferably, the solvent mixture is EtOAc/MTBE or DCM/MTBE.

When the crystalline compound containing pralsetinib is of Formula VII, the isolation according to step d) is obtained by adding a solvent selected from: esters, nitriles, chlorinated solvents and water, or mixtures thereof. When the solvent is an ester, it is preferably EtOAc. When the solvent is a nitrile, it is preferably ACN. When the solvent is a chlorinated solvent, it is preferably dichloromethane (DCM). Preferably, the solvent mixture is ACN/water.

Preferably, the compounds of Formula V, VI and VII are isolated according to step d) at a temperature of 25?C to 70?C, more preferably 25?C to 30?C.

As for step e), the basic solution is preferably an aqueous solution of a base chosen from: LiOH, NaOH, KOH, or mixtures thereof.

The solvent used in step e) is selected from alcohols, esters, chlorinated solvents, aromatic hydrocarbons, or mixtures thereof. Preferably, when the solvent is an ester, it is EtOAc. Preferably, when the solvent is an aromatic hydrocarbon, it is toluene. Preferably, when the solvent is an alcohol, it is selected from EtOH, MeOH, tert-butanol (t-BuOH). Preferably, when the solvent is a chlorinated solvent, it is dichloromethane. Preferably, the solvent mixture is selected from EtOH/DCM, MeOH/DCM, t-BuOH/DCM. More preferably, the solvent mixture is EtOH/DCM. Preferably, the solvent mixture is an alcohol/DCM mixture in an amount of 10/90 % to 50/50 % v/v.

With reference to the isolation of pralsetinib in amorphous form according to step f), it is preferably performed by distillation, lyophilization or spray-drying.

As for the distillation, it is carried out at a temperature of 25?C to 100?C, preferably from 70?C to 80?C. After the distillation, an antisolvent is added. This antisolvent is preferably chosen from alkanes, ethers. When the antisolvent is an alkane, it is preferably chosen from cyclohexane, n-heptane, n-hexane. When the antisolvent is an ether, it is preferably MTBE.

As already reported above, the invention also relates to crystalline compounds containing pralsetinib, having the formulas:

Formula V;

Formula VI.

The crystalline compound containing pralsetinib of Formula V is pralsetinib/CSA salt, and exhibits a powder X-ray diffraction pattern comprising at least one of the characteristic peaks, expressed in 2-theta (2?) values, at 5.7??0.2?, 10.8??0.2?, 13.8??0.2?, 17.0??0.2?, 19.4??0.2?. Preferably, the crystalline compound containing pralsetinib of Formula V exhibits a powder X-ray diffraction pattern comprising at least two of the characteristic peaks, expressed in 2-theta (2?) values, at 5.7??0.2?, 10.8??0.2?, 13.8??0.2?, 17.0??0.2?, 19.4??0.2?. More preferably, the pralsetinib-containing crystalline compound of Formula V exhibits a powder X-ray diffraction pattern comprising at least three of the characteristic peaks, expressed in 2-theta (2?) values, at 5.7??0.2?, 10.8??0.2?, 13.8??0.2?, 17.0??0.2?, 19.4??0.2?. Even more preferably, the pralsetinib-containing crystalline compound of Formula V exhibits a powder X-ray diffraction pattern comprising at least four of the characteristic peaks, expressed in 2-theta (2?) values, at 5.7??0.2?, 10.8??0.2?, 13.8??0.2?, 17.0??0.2?, 19.4??0.2?. In a preferred embodiment, the crystalline compound containing pralsetinib of Formula V exhibits a powder X-ray diffraction pattern comprising or consisting of characteristic peaks, expressed as 2-theta (2α) values, at 5.7α−0.2α, 10.8α−0.2α, 13.8α−0.2α, 17.0α−0.2α, 19.4α−0.2α.

Preferably, the crystalline pralsetinib/CSA salt of formula V further exhibits at least one of the characteristic peaks, expressed in 2-theta (2?) values, at 20.0??0.2?, 21.8??0.2?, 22.1??0.2?.

Preferably, the crystalline pralsetinib/CSA salt of Formula V shows the TGA of Figure 2.

According to a preferred embodiment, the crystalline pralsetinib-containing compound of Formula VI is in the form of a pralsetinib/TFA salt, and exhibits a powder X-ray diffraction pattern comprising at least one of the characteristic peaks, expressed as 2-theta (2β) values, at 6.1β−0.2β, 7.8β−0.2β, 14.3β−0.2β, 15.6β−0.2β, 17.7β−0.2β, 17.9β−0.2β, 22.1β−0.2β. Preferably, the crystalline compound containing pralsetinib of Formula VI exhibits a powder X-ray diffraction pattern comprising at least two of the characteristic peaks, expressed as 2-theta (2α) values, at 6.1α 0.2α, 7.8α 0.2α, 14.3α 0.2α, 15.6α 0.2α, 17.7α 0.2α, 17.9α 0.2α, 22.1α 0.2α. More preferably the crystalline compound containing pralsetinib of Formula VI exhibits a powder X-ray diffraction pattern comprising at least three of the characteristic peaks, expressed as 2-theta (2?) values, at 6.1??0.2?, 7.8??0.2?, 14.3??0.2?, 15.6??0.2?, 17.7??0.2?, 17.9??0.2?, 22.1??0.2?. Even more preferably the crystalline compound containing pralsetinib of Formula VI exhibits a powder X-ray diffraction pattern comprising at least four of the characteristic peaks, expressed as 2-theta (2?) values, at 6.1??0.2?, 7.8??0.2?, 14.3??0.2?, 15.6??0.2?, 17.7??0.2?, 17.9??0.2?, 22.1??0.2?. In a preferred embodiment, the crystalline compound containing pralsetinib of Formula VI exhibits a powder X-ray diffraction pattern comprising or consisting of the characteristic peaks, expressed as 2-theta (2α) values, at 6.1α 0.2α, 7.8α 0.2α, 14.3α 0.2α, 15.6α 0.2α, 17.7α 0.2α, 17.9α 0.2α, 22.1α 0.2α.

Preferably, the crystalline pralsetinib/TFA salt of Formula VI further exhibits a characteristic peak, expressed in 2-theta (2?) values, at 11.5??0.2?.

Preferably, the crystalline pralsetinib/TFA salt of Formula VI shows the TGA of Figure 4.

As already reported above, the invention also relates to a crystalline compound containing pralsetinib having Formula VII:

Formula VII.

The pralsetinib-containing crystalline compound of Formula VII is a pralsetinib/PGA cocrystal, and exhibits a powder X-ray diffraction pattern comprising at least one of the characteristic peaks, expressed in 2-theta (2?) values, at 6.4??0.2?, 8.5??0.2?, 13.3??0.2?, 14.9??0.2?, 18.2??0.2?. Preferably, the pralsetinib-containing crystalline compound of Formula VII exhibits a powder X-ray diffraction pattern comprising at least two of the characteristic peaks, expressed in 2-theta (2?) values, at 6.4??0.2?, 8.5??0.2?, 13.3??0.2?, 14.9??0.2?, 18.2??0.2?. More preferably the pralsetinib-containing crystalline compound of Formula VII exhibits a powder X-ray diffraction pattern comprising at least three of the characteristic peaks, expressed in 2-theta (2?) values, at 6.4??0.2?, 8.5??0.2?, 13.3??0.2?, 14.9??0.2?, 18.2??0.2?. Even more preferably the pralsetinib-containing crystalline compound of Formula VII exhibits a powder X-ray diffraction pattern comprising at least four of the characteristic peaks, expressed in 2-theta (2?) values, at 6.4??0.2?, 8.5??0.2?, 13.3??0.2?, 14.9??0.2?, 18.2??0.2?. In a preferred embodiment, the crystalline compound containing pralsetinib of Formula VII exhibits a powder X-ray diffraction pattern comprising or consisting of the characteristic peaks, expressed as 2-theta (2α) values, at 6.4α−0.2α, 8.5α−0.2α, 13.3α−0.2α, 14.9α−0.2α, 18.2α−0.2α.

Preferably, the crystalline pralsetinib/PGA cocrystal of Formula VII further exhibits at least one of the peaks, expressed in 2-theta (2?) values, at 19.1??0.2?, 22.8??0.2?, 23.7??0.2?, 27.2??0.2?.

Preferably, the crystalline pralsetinib/PGA cocrystal of Formula VII shows the TGA of Figure 6. List of abbreviations

1. CSA: (1S)-(+)-10-camphorsulfonic acid

2. TFA: Trifluoroacetic acid

3. XRPD: X-ray powder diffraction

4. DSC: Differential Scanning Calorimetry

5. TGA: Thermogavimetric analysis

6. LiOH: Lithium hydroxide

7. NaOH: Sodium hydroxide

8. KOH: Potassium hydroxide

9. MeOH: Methanol

10. EtOH: Ethanol

11. t-BuOH: tert-butyl alcohol

12. THF: Tetrahydrofuran

13. MTBE: Methyl-tert-butyl ether

14. DCM: Dichloromethane

15. ACN: Acetonitrile

16. PyBOP: Benzotriazole-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate

17. TEA: Triethylamine

18. DIPEA: N,N-Diisopropylethylamine

19. DMAc: Dimethyl acetamide

20. EtOAc: Ethyl acetate

Examples

Example 1: Synthesis of the compound of Formula III (cyclohexanecarboxylic acid, 1-methoxy-4-[4-methyl-6-[(5-methyl-1H -pyrazol-3-yl)amino]-2-pyrimidinyl]).

To a solution of the compound of Formula II (cyclohexanecarboxylic acid, 1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]-methyl ester) (800.0 g, 2.2 mol) in a mixture of THF/EtOH/H2O (20.0 L), LiOH.H2O (186.78 g, 4.5 mol) was added at room temperature. The reaction mixture was stirred for 16 h. The reaction termination T? was monitored by TLC or HPLC. The solvent was distilled off under vacuum and the residue was suspended in a mixture of THF/EtOH (8.0 L). The product was filtered and the wet cake was suspended in MeOH (8.0 L). The pH was ? was then adjusted to 5.0 using dilute HCl, the product was filtered and dried in a Vacuum Tray Dryer to give a pure compound of Formula III (cyclohexanecarboxylic acid, 1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl) (640 g, yield 83.3%).

Example 2: Synthesis of the compound of Formula III (cyclohexanecarboxylic acid, 1-methoxy-4-[4-methyl-6-[(5-methyl-1H -pyrazol-3-yl)amino]-2-pyrimidinyl]).

To a solution of the compound of Formula II (cyclohexanecarboxylic acid, 1-methoxy-4-[4-methyl-6-[(5-methyl-1H -pyrazol-3-yl)amino]-2-pyrimidinyl]-, methyl ester) (5.0 g, 0.01 mol) in a THF/H2O mixture (67.5 mL), LiOH.H2O (1.17 g, 0.03 mol) was added. The reaction mixture was heated at 50-60?C for 12 h. The termination of the reaction was monitored by HPLC. The solvent was distilled off under vacuum, the residue was suspended in MeOH (50 mL), and the pH was adjusted to 5.0. The product was filtered and dried in a Vacuum Tray Dryer. to give a pure compound of Formula III (cyclohexanecarboxylic acid, 1-methoxy-4-[4-methyl-6-[(5-methyl-1H -pyrazol-3-yl)amino]-2-pyrimidinyl]) (4.3 g, yield 90.0%).

Example 3: Synthesis of the compound of Formula III (cyclohexanecarboxylic acid, 1-methoxy-4-[4-methyl-6-[(5-methyl-1H -pyrazol-3-yl)amino]-2-pyrimidinyl]).

To a solution of the compound of Formula II (cyclohexanecarboxylic acid, 1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]-, methyl ester) (5.0 g, 0.01 mol) in a mixture of THF/H2O (67.5 mL), NaOH (1.11 g, 0.03 mol) was added. The reaction mixture was heated at 50-60?C for 12 h. The end of the reaction was monitored by HPLC. The solvent was distilled under vacuum, the residue was suspended in MeOH (50 mL), and the pH was adjusted to 5.0. The product was filtered and dried in a Vacuum Tray Dryer. to give the pure compound of Formula III (cyclohexanecarboxylic acid, 1-methoxy-4-[4-methyl-6-[(5-methyl-1H -pyrazol-3-yl)amino]-2-pyrimidinyl]) (4.5 g, yield 93.75%).

Example 4: Synthesis of pralsetinib/CSA salt of Formula V.

A suspension of the compound of Formula III was charged with (cyclohexanecarboxylic acid, 1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]) (5 g, 14.47 mmol) in DMAc (100 mL), DIPEA (20.17 mL, 115 mmol), and the compound of Formula IV ((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethanamine hydrochloride) (4.85 g, 17.37 mmol). The suspension was stirred for 30 min, then PyBOP (11.30 g, 21.71 mmol) was added. The reaction mixture was stirred for 2 h, then PyBOP (1.51 g, 2.89 mmol) was added and stirred for 1 hour. PyBOP (1.51 g, 2.89 mmol) was further added and stirred for another hour. The termination of the reaction was monitored by HPLC. The reaction mixture was diluted with H2O (200 mL) and the product was extracted with EtOAc (200 mL). The organic layer was washed with 9.0% aqueous NaHCO3 followed by 15.0% brine. The organic layer was distilled to give an oily residue only to which MeOH (40 mL) and H2O (10 mL) were added, followed by CSA (2.7 g, 11.58 mmol). The reaction mixture was stirred for 24 h and the solvent was distilled off. Then, ACN/H2O (150 mL) was washed off. was added to the residue and the mixture was stirred for 12-24 hours to obtain a suspension.

Finally, the product was filtered to obtain the CSA salt of pralsetinib (Formula V) with yield >90.0% and purity >95%. The XPRD pattern is shown in Table 1. Example 5: Synthesis of pralsetinib/TFA salt of Formula VI.

A suspension of the compound of Formula III (cyclohexanecarboxylic acid, 1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]) (5.0 g, 14.47 mmol) in DMAc (100 mL), DIPEA (20.17 mL, 115 mmol) and the compound of Formula IV (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethanamine hydrochloride) (4.85 g, 17.37 mmol) were charged. The suspension was stirred for 30 min, then PyBOP (11.30 g, 21.71 mmol) was added. The reaction mixture was stirred for 2 h and the end of the reaction was monitored by HPLC. The reaction mixture was diluted with H2O (200 mL) and the product was extracted with EtOAc (200 mL). The organic layer was washed with 9.0% aqueous NaHCO3 followed by 15.0% brine. The organic layer was distilled to give only an oily residue to which EtOAc (50 mL) was added and stirred to give a clear solution. TFA (2.14 g, 18.79 mmol) was added to the solution and stirred for 2-3 hours until precipitation occurred. Then, MTBE (50 mL) was added and the slurry was further stirred for 2-3 hours. The product was filtered and dried to give pralsetinib/TFA salt (Formula VI) in >90.0% yield and HPLC Purity >96.00%. The XPRD pattern is shown in Table 2.

Example 6: Synthesis of pralsetinib/TFA salt of Formula VI.

A suspension of the compound of Formula III (cyclohexanecarboxylic acid) was loaded with 1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]) (5.0 g, 14.47 mmol) in DMAc (100 mL), DIPEA (20.17 mL, 115 mmol), and the compound of Formula IV (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethanamine hydrochloride (4.85 g, 17.37 mmol). The suspension was stirred for 30 min, then PyBOP (11.30 g, 21.71 mmol) was added. The reaction mixture was stirred for 2 h, and the end of the reaction was monitored by HPLC. The reaction mixture was diluted with H2O (200 mL) and the product was extracted with EtOAc (200 mL). The organic layer was washed with 9.0% NaHCO3 followed by 15.0% brine. The organic layer was distilled to give an oily residue which was stripped with DCM (25 mL) and then DCM (50 mL to 100 mL) was added and stirred to give a clear solution. To the solution was added TFA (2.14 g, 18.79 mmol) and stirred for 2-3 h until precipitation occurred. Then, MTBE (50 mL to 100 mL) was added to the slurry and stirred for a further 2-3 h. The product was was filtered and dried to give pralsetinib/TFA salt (Formula VI) with yield >90.0% and HPLC Purity >98.00%.

Example 7: Synthesis of pralsetinib/PGA cocrystal of Formula VII.

A suspension of the compound of Formula III (cyclohexanecarboxylic acid, 1-methoxy-4-[4-methyl-6[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]) (2.0 g, 5.79 mmol) in DMAc (40 mL), DIPEA (8.0 mL, 46.32 mmol) and compound of Formula IV (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethanamine hydrochloride) (1.97 g, 8.10 mmol) were charged. The suspension was stirred for 30 min and PyBOP (4.52 g, 8.68 mmol) was added. The reaction mixture was stirred for 2 h and the end of the reaction was monitored by HPLC. The reaction mixture was stirred for 2 h and the end of the reaction was monitored by HPLC. was diluted with H2O (80 mL) and the product extracted with ethyl acetate (80 mL). The organic layer was washed with 9.0% aqueous NaHCO3 followed by 15.0% brine. The organic layer was distilled to give only an oily residue to which EtOAc (20 mL) was added and stirred to a clear solution. Pyroglutamic acid (0.97 g, 7.5 mmol) was added and the reaction mixture was stirred for 12 h. The product was filtered and dried to give pralsetinib/PGA cocrystal (Formula VII) in >90.0% yield and HPLC purity >96.0%. The XPRD pattern is shown in Table 3.

Example 8: pralsetinib in amorphous form (Formula I) from pralsetinib/CSA salt (Formula V).

Pralsetinib/CSA salt (Formula V) was dissolved in DCM (10 volumes). The resulting solution was washed with 10% aqueous NaOH (10 volumes). The organic layer was distilled to give an amorphous, foamy solid which was dissolved in DCM (10 volumes) with 10-50% EtOH to give a clear solution. The solution was filtered to remove particles and vacuum distilled at temperatures of 25-80?C with or without stirring to completely remove solvents, then cooled to 25-30?C and cyclohexane (10 volumes) was added, stirring for 2 hours. The product was filtered and dried in VTD to obtain amorphous pralsetinib (Formula I) in >90.0% yield.

Example 9: pralsetinib (Formula I) in amorphous form from pralsetinib/TFA salt (Formula VI).

Pralsetinib/TFA salt (Formula VI) (5.0 g, 7.73 mmol) was dissolved in DCM (50 ml). The resulting solution was washed with 10% aqueous NaOH (50 ml). The organic layer was distilled to give an amorphous, foamy solid which was dissolved in 10-50% EtOH in DCM (50 ml) to give a clear solution. The solution was filtered to remove particles and distilled under vacuum at 25-80?C with or without stirring to completely remove solvents, then cooled to 25-30?C and cyclohexane (50 ml) was added, stirring for 2 hours. The product was filtered and dried in VTD to afford amorphous pralsetinib (Formula I) in >90.0% yield.

Example 10: pralsetinib amorphous form (Formula I) from pralsetinib/TFA salt (Formula VI).

Pralsetinib/TFA salt (Formula VI) (5.0 g, 7.73 mmol) was suspended in ethyl acetate (50 ml) and 10% NaOH aqueous solution (50 ml) was added and the mixture was stirred. The organic layer was separated to give a pralsetinib solution, then filtered to remove particles and distilled under vacuum at 25-80°C with or without stirring to completely remove solvents, then cooled to 25-30°C and cyclohexane (50 ml) was added, stirring for 2 hours. The product was filtered and dried in VTD to give amorphous pralsetinib (Formula I) in >90.0% yield.

Example 11: pralsetinib amorphous form (Formula I) from pralsetinib/PGA cocrystal (Formula VII).

Pralsetinib/PGA cocrystal (Formula VII) was dissolved in DCM (10 volumes). The resulting solution was washed with 10% aqueous NaOH (10 volumes). The organic layer was distilled to give an amorphous, foamy solid which was dissolved in 10-50% EtOH in DCM (10 volumes) to give a clear solution. The solution was filtered to remove particles and distilled under vacuum at 25-80°C with or without stirring to give a foamy solid. After cooling to 25-30°C, cyclohexane (10 volumes) was added and stirred for 2 hours. The product was filtered and dried in VTD to give pralsetinib (Formula I) in an amorphous form with a yield >90.0%.

Analysis 1: XRPD Pattern of Pralsetinib/CSA Salt of Formula V

Table 1

Analysis 2: XRPD Pattern of Pralsetinib/TFA Salt of Formula VI

Table 2

Analysis 3: XRPD Pattern of Pralsetinib/PGA Cocrystal of Formula VII

Table 3

Claims (18)

1. A process for preparing Formula I pralsetinib Formula I, in amorphous form, said process comprising: a) react the compound of Formula II Formula II with a base in a solvent to obtain a compound of Formula III, Formula III where the solvent is chosen from an organic solvent, water or a combination thereof; b) isolate the compound of Formula III at a pH ranging from 2 to 9; c) react the isolated compound of Formula III with a compound of Formula IV Formula IV in the presence of a coupling agent, a base and a polar aprotic solvent to obtain pralsetinib in solution form; d) isolate a crystalline compound containing pralsetinib by reacting pralsetinib in the form of solution obtained in step c) with an acid chosen from: (1S)-(+)-10-camphorsulfonic acid (CSA), trifluoroacetic acid (TFA) and pyroglutamic acid (PGA); e) suspend the isolated crystalline compound containing pralsetinib obtained in step d) in a solvent chosen from alcohols, esters, aromatic hydrocarbons, chlorinated solvents or mixtures thereof, and add to the suspension thus obtained a basic solution to obtain a solution of pralsetinib as free base; f) isolate pralsetinib in amorphous form from the pralsetinib free base solution obtained in step e). 2. The process according to claim 1, wherein in step a) the solvent is selected from: alcohols, preferably methyl alcohol (MeOH) or ethyl alcohol (EtOH); ethers, preferably tetrahydrofuran (THF); and water, or mixtures thereof. 3. The process according to claim 1 or 2, wherein in step b) the pH is from 2 to 5. 4. The process according to any of the preceding claims, wherein in step c) the coupling agent is selected from benzotriazole-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBOP), N,N,N?,N?-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate (TBTU), N-ethyl-N?-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), preferably the coupling agent is PyBOP. 5. The process according to any of the preceding claims, wherein in step c) the base is selected from N,N-diisopropylethylamine (DIPEA) or triethylamine (TEA). 6. The process according to any of the preceding claims, wherein in step c) the polar aprotic solvent is selected from: N,N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF) or mixtures thereof. 7. The process according to any of the preceding claims, wherein the crystalline compound containing pralsetinib is represented by one of the following formulas: Formula V Formula VI Formula VII where the Formula V intermediate is pralsetinib/CSA salt, the Formula VI intermediate is pralsetinib/TFA salt, and the Formula VII intermediate is pralsetinib/PGA cocrystal, preferably the Formula VI intermediate is pralsetinib/TFA salt. 8. The process according to claim 7, wherein in step d) the crystalline compound containing pralsetinib of Formula V is isolated by adding a solvent selected from: alcohols, preferably selected from MeOH and EtOH; esters, preferably EtOAc; nitriles, preferably acetonitrile (ACN); and water; or mixtures thereof. 9. The process according to claim 7, wherein in step d) the crystalline compound containing pralsetinib of Formula VI is isolated by adding a solvent selected from: esters, preferably ethyl acetate (EtOAc); nitriles, preferably ACN; ethers, preferably tert-butyl methyl ether (MTBE); chlorinated solvents, preferably dichloromethane (DCM); and water; or mixtures thereof. 10. The process according to claim 7, wherein in step d) the crystalline compound containing pralsetinib of Formula VII is isolated by adding a solvent selected from: esters, preferably EtOAc; nitriles, preferably ACN; chlorinated solvents, preferably dichloromethane; and water; or mixtures thereof. 11. The process according to any of the preceding claims, wherein in step e) the solvent is selected from: alcohols, preferably selected from EtOH, MeOH, tert-butanol (t-BuOH); esters, preferably EtOAc; chlorinated solvents, preferably dichloromethane; aromatic hydrocarbons, preferably toluene; or mixtures thereof. 12. The process according to any of the preceding claims, wherein in step f) isolating pralsetinib in amorphous form is performed by distillation, freeze-drying or spray-drying. 13. A crystalline compound containing pralsetinib, having Formula V: Formula V. 14. The crystalline compound containing pralsetinib of Formula V according to claim 13, having a powder X-ray diffraction pattern comprising at least one of the characteristic peaks, expressed in 2-theta (2?) values, at 5.7??0.2?, 10.8??0.2?, 13.8??0.2?, 17.0??0.2?, 19.4??0.2?. 15. A crystalline compound containing pralsetinib, having Formula VI: Formula VI. 16. A crystalline compound containing pralsetinib of Formula VI according to claim 15, having a powder X-ray diffraction pattern comprising at least one of the characteristic peaks, expressed in 2-theta (2?) values, at 6.1??0.2?, 7.8??0.2?, 14.3??0.2?, 15.6??0.2?, 17.7??0.2?, 17.9??0.2?, 22.1??0.2?. 17. A crystalline compound containing pralsetinib, having Formula VII Formula VII. 18. The crystalline compound containing pralsetinib of Formula VII according to claim 17, having a powder X-ray diffraction pattern comprising at least one of the characteristic peaks, expressed in 2-theta (2?) values, at 6.4??0.2?, 8.5??0.2?, 13.3??0.2?, 14.9??0.2?, 18.2??0.2?.